It is controversial as to whether or not nitroglycerin (NTG) increases subendocardial myocardial blood flow (SMBF), and if it does, whether arterial or venous blood flow is increased in patients with coronary artery disease. This study was performed to examine NTG-induced changes in SMBF.
Changes in SMBF induced by NTG (200 μg, i.v.) were examined by cardioscopy in 58 left ventricular wall segments of 58 patients with coronary artery disease. NTG-induced red and purple endocardial colors were defined as increased arterial and venous SMBF, respectively. Endocardial color before NTG administration was classified into brown, light brown, pale and white. Endomyocardial biopsy of the observed portion and ²⁰¹Tl scintigraphy were performed in 40 of these patients immediately after cardioscopy and several days after cardioscopy, respectively.
Upon administration of NTG, SMBF increased in 48 of 58 wall segments; arterial SMBF in 34 and venous SMBF in 12 wall segments; arterial SMBF in all 24 brown to light brown segments; venous SMBF, arterial SMBF and no change in 12, 10 and 5 of pale segments, respectively; and no change in all 10 white wall segments. ²⁰¹Tl-scintigraphy and endomyocardial biopsy revealed that brown, light brown, pale and white endocardial color represented no ischemia, mild ischemia, severe ischemia and fibrosis, respectively.
NTG caused an increase in either arterial or venous SMBF depending on control endocardial color, wall motion and severity of coronary stenosis.

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Even patients without vasospastic angina show vasoconstriction after intracoronary ergonovine administration. We evaluated the determinants of coronary artery responsiveness to ergonovine in such patients.
In 165 patients with no provoked electrocardiographic changes or ischemic chest pain during an intracoronary ergonovine test, total cholesterol, triglycerides (TG), high density lipoprotein cholesterol (HDL), and low density lipoprotein cholesterol (LDL) were correlated with the arterial luminal diameters before and after ergonovine infusion and after nitroglycerin injection by quantitative coronary angiography analysis.
The mean and maximal basal tone (ie, percent change between baseline luminal diameter and diameter after nitroglycerin) were 7.0 ± 9.9% and 27.9 ± 10.8%, respectively. The mean and maximal responsiveness to ergonovine (ie, percent change between minimal diameter during ergonovine infusion and diameter after nitroglycerin) were 30.3 ± 13.6% and 52.7 ± 16.0%, respectively. The TG level (r = 0.191, P = 0.016) and TG/HDL ratio (r = 0.182, P = 0.021) were positively correlated with the basal tone, whereas LDL level (r = 0.155, P = 0.048) and LDL/HDL ratio (r = 0.172, P = 0.030) were positively correlated with the responsiveness to ergonovine. By multivariate analysis, LDL level, LDL/HDL ratio, and smoking were independent predictors of more than 50% responsiveness to ergonovine.
Serum lipid profile and smoking influence the basal tone and responsiveness to ergonovine of coronary artery in patients without vaospastic angina.

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Low density lipoproteins (LDLs) are heterogeneous aggregations of molecules of different particle sizes, and small-size LDLs are more potent risk factors for atherosclerosis. We examined the qualitative characteristics of LDLs in patients with stable coronary artery disease (CAD) receiving statin therapy. LDL-particle size was estimated based on the LDL-cholesterol/apolipoprotein B ratio (LDL-C/apoB) in 214 age-adjusted men receiving statin therapy. The LDL-C/apoB ratio was significantly lower in the CAD (+) group (n = 107) than in the CAD (-) group (n = 107) (median, 1.17 versus 1.19, P = 0.0095). LDL-C/apoB was significantly lower in patients with serum TG ≥ 150 mg/dL than in those with serum TG < 150 mg/dL, and in patients with serum HDL-C < 40 mg/dL than in those with serum HDL-C ≥ 40 mg/dL (1.06 versus 1.18, P = 0.012; 1.08 versus 1.22, P = 0.0023). Stepwise logistic regression analysis revealed that elevated serum TG was an independent predictor for smaller sizes of LDLs, both in the overall subjects (β : -0.165, P = 0.02) as well as in the subset with serum LDL-C < 100 mg/dL (β : -0.252, P = 0.011). This study demonstrated that not only the absolute serum LDL-C level, but also the qualitative characteristics of LDL may be monitored for secondary prevention of CAD. Such monitoring is particularly important in patients with elevated serum TG levels, which is associated with smaller sizes of LDL-particles.

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Diabetes mellitus has a greater effect on mortality rates due to coronary artery disease in women than in men. Although women undergoing coronary intervention in general have a higher frequency of adverse outcomes than men, the effect of gender among diabetic patients on clinical outcomes after percutaneous coronary intervention (PCI) has not been well established in the drug-eluting stent (DES) era. We have investigated the impact of gender on long-term clinical outcome in these high risk populations. We enrolled 404 consecutive patients (74 women and 330 men) with diabetes mellitus who underwent elective PCI (85% with DES). We evaluated the incidence of major adverse cardiac events (MACE), which is a composite of total all-cause death, acute coronary syndrome (ACS), and target lesion revascularization (TLR) during a period of 4 years after coronary intervention. The women were significantly older, more likely to have dyslipidemia, and had significantly higher systolic blood pressure and LDL-C values than men. The use of insulin and angiotensin receptor blockers was more frequent among the women (32.4% versus 21.0%, P = 0.04 and 60.8% versus 39.8%, P < 0.01, respectively). The angiographic profiles of both were comparable. At four-year clinical follow-up, cumulative incidence of MACE was identical between the women and the men (16.2% versus 15.5%, P = 0.90; adjusted HR 1.23, 95% CI 0.61-2.50, P = 0.56). Although the baseline characteristics of the women were worse, clinical outcomes did not significantly differ between women and men among diabetic patients after elective PCI.

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Although bepridil is effective for conversion of long-lasting persistent atrial fibrillation (AF) to sinus rhythm, it sometimes takes a long time to interrupt AF and there is no feasible index to predict its efficacy.
In 60 patients with long-lasting persistent AF, bepridil (100-200 mg/day) was administered and continued for 8 weeks while body surface ECG was recorded every 2 weeks. The fibrillation cycle length (FCL) was evaluated using the spectral analysis of the fibrillation waves in each ECG. AF was interrupted in 32 patients receiving bepridil. The conversion was observed at 2 weeks in 4, at 4 weeks in 7, at 6 weeks in 7, and at 8 weeks in 14 patients. When comparing these responders and nonresponders, clinical background characteristics other than the dosage of bepridil did not show any difference and neither did temporal changes in QT parameters and heart rate. In contrast, the FCL and ΔFCL (prolongation in FCL from baseline) became significantly larger in responders than in nonresponders at later observation points (FCL: 177 ± 17 versus 164 ± 19 ms, P = 0.018, and ΔFCL: 38 ± 16 versus 22 ± 12 ms, P < 0.001, at 4-week point; FCL: 188 ± 17 versus 169 ± 19 ms, P = 0.004, and ΔFCL: 49 ± 18 versus 27 ± 14 ms, P < 0.001, at 6-week point).
Repetitive evaluation of FCL using spectral analysis of fibrillation waves can be a feasible index to predict the efficacy of bepridil therapy.

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There is little information available on the benefits of selection of statins as upstream therapy for the prevention of paroxysmal atrial fibrillation (AF). We compared the efficacy and safety of atorvastatin (A-group, n = 43) and pravastatin (P-group, n = 41) as upstream therapy in patients with paroxysmal AF and dyslipidemia. A total of 84 patients (45 men, mean age, 66 ± 9 years, mean follow-up, 49 ± 32 months) were retrospectively assigned to receive atorvastatin (n = 41;10 mg/day) or pravastatin (n = 43 ; 10 mg/day). Survival rates free from AF recurrence at 1, 6, 12, and 24 months were 93%, 74%, 60%, and 53% in A-group, and 88%, 49%, 37%, and 29%, respectively, in P-group (P = 0.029, A-group versus P-group). Survival rates free from conversion to permanent AF at 12, 36, 60, and 90 months were 100%, 100%, 98%, and 95% in A-group, and 100%, 95%, 88%, and 83%, respectively, in P-group (P = 0.063, A-group versus P-group). Using a logistic regression model, atorvastatin was found to be associated with a significantly reduced risk of AF recurrence in comparison to pravastatin (unadjusted odds ratio [OR] = 0.27, 95% confidence interval 0.11-0.68, P = 0.005). This association remained significant after adjustment for potentially confounding variables (OR = 0.26, 95% CI 0.08-0.86, P = 0.027). Using a logistic regression model, atorvastatin was not associated with a significantly reduced risk of converting to permanent AF in comparison to pravastatin (unadjusted OR = 0.29, 95% CI 0.05-1.50, P = 0.138), but this association did show a significant difference after adjustment for potentially confounding variables in a multivariate model (OR = 0.08, 95% CI 0.06-0.96, P = 0.046). Adverse effects requiring discontinuation of statins were observed in 1 case (2%, myalgia) in A-group, and 1 case (2%, elevation in CPK level ≥ 500 IU/L) in P-group, respectively (P = NS, A-group versus P-group). Atorvastatin, a lipophilic statin, was considered to be more effective in preventing recurrence of paroxysmal AF and conversion to permanent AF than pravastatin, a hydrophilic statin.

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The relationship between mild-to-moderate renal dysfunction and cardiac diastolic dysfunction and cardiac events in patients with nonischemic dilated cardiomyopathy (NDCM) has not been fully elucidated. The aim of this study was to investigate the relationship between renal and cardiac function, as well as clinical outcome in patients with NDCM.
We measured plasma BNP and eGFR, and performed cardiac catheterization in 135 patients with NDCM. LV dP/dt_maxand T_1/2 were determined as indexes of LV contractility and isovolumic relaxation, respectively. During a mean follow-up of 4.8 years, we monitored all patients for the occurrence of cardiac events, which were defined as cardiac death (from worsening HF or sudden death) and unscheduled admission for decompensated HF.
Patients were classified into 3 groups on the basis of eGFR (mL min^-1 1.73 m^-2): eGFR ≥ 90 (n = 23, group A), 60 ≤ eGFR < 90 (n = 70, group B), and 30 ≤ eGFR < 60 (n = 42, group C). Whereas LV dP/dt_max did not significantly differ among the 3 groups, T_1/2 was significantly longer in groups B and C than in group A (P < 0.01). Event-free survival in group C was significantly lower than that in groups A and B (P = 0.014, log-rank test).
These results suggest that even mild renal dysfunction is associated with LV isovolumic relaxation impairment. In addition, moderate impairment of renal function is independently associated with cardiac events in patients with NDCM.

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Clinical hard outcomes (death and myocardial infarction) between bypass surgery (CABG) and percutaneous coronary intervention (PCI) are generally similar, whereas target vessel revascularization and angina relief are often superior with CABG. However, there are no data regarding 10-year long-term clinical outcomes between the two procedures in metabolic syndrome (MetS). The aim of this study was to assess the long-term outcomes of CABG and plain old balloon angioplasty (POBA) in MetS patients. We enrolled 869 patients, 318 (36.6%) and 551 (63.4%) of whom underwent POBA and CABG, respectively. During follow-up (10.1 ± 3.5 years), 221 patients died (118 cardiovascular deaths) and 256 underwent revascularization. We predicted the probability of undergoing CABG using propensity analysis. Unadjusted survival was significantly lower in the CABG group because of unfavorable baseline characteristics. After adjusting for baseline variables including propensity score, POBA and CABG did not differ in terms of all cause (hazard ratio [HR] of CABG, 1.46; P = 0.132) and cardiovascular mortality (HR of CABG, 1.11; P = 0.757). However, the risk of subsequent revascularization was significantly lower in the CABG group than in the POBA group (HR of CABG, 0.15; P < 0.001). This study demonstrated that CABG is superior to POBA in terms of target vessel revascularization in MetS patients, whereas there were no significant differences in mortality after adjusting for baseline variables including propensity score.

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Pulmonary thromboendarterectomy (PEA) is a curative therapy for chronic thromboembolic pulmonary hypertension (CTEPH), but the postoperative mortality remains unsatisfactory (4-10%). Residual pulmonary hypertension is the most common cause of perioperative death. Although PEA specimens seem to contain lesions responsible for hemodynamic improvement, relevant histopathological findings have still to be identified.
The aim of this study was to identify histopathological findings that predict postoperative residual pulmonary hypertension after PEA.
PEA specimens obtained from 51 consecutive patients with CTEPH were histopathologically assessed. The patient characteristics and disease location were reviewed by medical records. The associations with residual pulmonary hypertension were analyzed.
The mean values of preoperative and postoperative vascular resistance (PVR) were 1142 ± 454 and 496 ± 368 dynes•sec/cm^-5, respectively. Twenty of 51 patients (39%), including 2 patients who died, continued to have residual pulmonary hypertension (PVR ≥ 500 dynes•sec/cm^-5). Statistical tests indicated that male, proximal disease type and the presence of histopathological multiple recanalized thrombus were associated with good surgical outcome (PVR < 500 dynes•sec/cm^-5). The positive and negative predictive values for surgical outcome estimated by the presence of multiple recanalized lesions were higher than the values estimated by proximal disease type (85% and 88% versus 73% and 71%, respectively). Moreover, the number of multiple recanalize lesions was significantly correlated to the reduction in PVR (P = 0.03).
The presence of histopathological multiple recanalized lesions was significantly associated with a decrease in PVR after PEA. Histopathological study may be a potent diagnostic strategy for accurately predicting surgical outcome in the early perioperative period.

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Downregulation of CD4+CD25+ regulatory T lymphocytes (Treg) has been found in local atherosclerotic lesions and in patients with myocardial infarction (MI). However, the roles of Treg in MI and the following inflammatory response have not yet been well elucidated. Therefore, we hypothesized that adoptive transfer of Treg could attenuate the postinfarction inflammatory response protecting from adverse remodeling, and we attempted to elucidate the mechanism of delayed heart failure after MI. To clarify the role of Treg in MI, we used a murine MI model and administered a single intravenous injection of Treg (1 × 10⁵) (treatment, n = 6) or saline (control, n = 7) and sacrificed the mice on day 14. Echocardiograms revealed that Treg improved LV contraction after MI. Histopathology also showed that Treg negated MI-induced LV remodeling. RT-PCR demonstrated that the mRNA levels of IFN-gamma in hearts were lower and Foxp3 in spleens were higher in the treatment group than in the control group. We observed that adoptive Treg transfer could attenuate MI-induced cardiac remodeling through the IFN-gamma and Foxp3 alteration.

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Plasminogen activator inhibitor-1 (PAI-1) contributes to cardiac ventricular remodeling because migration of inflammatory cells and attenuation of extracellular matrix degradation are caused by plasmin and matrix metalloproteinase. However, the roles of PAI-1 in myocardial ischemia reperfusion (I/R) injury and the following inflammatory response have not yet been well elucidated. To clarify the role of PAI-1 in myocardial I/R injury, we used a specific PAI-1 inhibitor (IMD-1622) in a rat model. The left anterior descending coronary artery was ligated and reperfusion was performed by loosening the suture after 30 minutes of arterial occlusion. A single administration of IMD-1622 (20 mg/kg) or vehicle was given intraperitoneally and then the rats were sacrificed on day 1 or day 14 after I/R. Blood pressure, echocardiograms, histopathology, and molecular examination were performed. The examinations revealed that PAI-1 inhibitor showed limited effects on cardiac dysfunction and ventricular remodeling after I/R. We conclude that the pharmacological inhibition of PAI-1 may not affect ventricular remodeling after myocardial I/R injury.

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The combined effects of disopyramide (DP) and erythromycin (EM) on ventricular repolarization and the inciden-ces of ventricular premature contractions (VPCs) and torsades de pointes (TdP) were investigated in 12 anesthetized dogs with complete atrioventricular block. Monophasic action potentials (MAPs) were measured from the left and right ventricular (LV and RV) endocardium. The right or left ventricle was paced at a cycle length of 750-1000 msec. Dogs were divided into 2 groups and given either intravenous DP at 3 mg/kg and then intravenous EM at 50 mg/kg (group 1, n = 8), or intravenous EM at 50 mg/kg and then intravenous DP at 3 mg/kg (group 2, n = 4). MAP duration at 90% repolarization (MAPD₉₀) was measured before drug administration (baseline) and again after administration of each drug. RV MAPD₉₀ and LV MAPD₉₀ increased significantly (P < 0.02) after administration of each drug in group 1 (RV MAPD₉₀: from 247.0 ± 36.3 [baseline] to 283.5 ± 38.3 to 321.8 ± 56.7; LV MAPD₉₀: from 262.6 ± 49.1 (baseline) to 296.1 ± 58.8 to 351.0 ± 80.6). Early afterdepolarizations developed in 2 group 1 dogs after administration of DP and in 4 additional dogs after administration of EM. Frequent VPCs occurred in 1 dog after administration of DP and in 2 additional dogs after administration of EM, and TdP and ventricular tachycardias developed in 2 of the 3 dogs after administration of EM. Similar trends occurred in group 2. These results indicate a potentially fatal interaction between DP and EM administered in clinically relevant doses.

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A 33-year-old Japanese man with atrial tachycardia visited our clinic. He regularly consumed daily alcohol with cola, one cup of regular coffee, and a candy containing 0.7 mg of caffeine per tablet. After stopping his caffeine intake, his arrhythmia ameliorated. Since caffeine might be associated with his arrhythmia, a caffeine load test (equivalent to his daily intake of caffeine) was performed for 4 days. Atrial tachycardia time from a Holter recording was 44.2 minute/day before the caffeine load, compared with 215.2 minute/day during the caffeine load. Plasma caffeine concentration before and during caffeine loading was 3.1 mg/dL and 5.4 mg/dL, respectively. Caffeine use seemed to be an important factor for his atrial tachycardia, since his arrhythmia became worse during caffeine load testing and was ameliorated after the cessation of caffeine.

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Nemaline myopathy is a representative form of congenital myopathy, and is characterized by nemaline bodies in muscle fibers. Here we report a 47-year-old man with congenital nemaline myopathy complicated with dilated cardiomyopathy-related heart failure, and restrictive respiratory failure. The complication of dilated cardiomyopathy in nemaline myopathy has rarely been reported. In this case, nemaline bodies were detected in the cardiac muscle fibers, demonstrating the presence of underlying disease-related myocardial degeneration. The patient responded to the combination of conventional therapy for heart failure including β-blocker and noninvasive continuous positive-pressure ventilation for respiratory failure. His general condition has been stable during a 10-month follow up period.

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